PROJECT SUMMARY Glioblastoma (GBM) is the most common and aggressive primary brain cancer with limited treatment options. The median survival for GBM patients is less than 15 months after diagnosis, and tumors recur in over 90% of patients after treatment with the standard of care consisting of surgical resection, radiation, and chemotherapy. Most preclinical research for GBM is conducted in rodents, which have vastly different anatomy to humans, particularly regarding brain size and structure, making surgery and imaging challenging. Rodents also differ drastically from humans in physiology, metabolism, and genetics, and therefore, response to therapies in rodent preclinical GBM models is not always predictive of success in human clinical trials. Many GBM therapies are being actively investigated in clinical trials. As of December 13, 2018, the U.S. National Library of Medicine has records for 1,335 clinical trials for GBM, 771 of which have been completed, suspended, terminated, or withdrawn, and yet none of these have improved the standard of care since 2005. A large animal preclinical GBM model that more closely resembles the human disease and is therapeutically predictive will improve GBM patient survival by ensuring the safety and efficacy of new therapies prior to human use. Pigs brains are much more similar to human in size and structure than rodents?, making them ideal for testing therapies, performing surgical techniques, and developing imaging procedures. To generate a relevant large animal model of GBM, we propose to make the same genetic alterations in brain cells of live pigs that are most frequently mutated in human GBM. This will be the first large animal model to replicate the genetic landscape of human GBM in an immunocompetent pig, which will allow the study of tumor development, progression and recurrence and enable the testing and refinement of promising targeted and immune therapies for GBM. This technology will also be highly adaptable, allowing various combinations of oncogenes and tumor suppressor genes to be altered, allowing for rapid production of reliable swine models of multiple subtypes of human GBM. This swine model of GBM will allow the development and testing of novel imaging technology, surgical techniques, devices, targeted drugs, and immune therapies before or in parallel to clinical trials, improving clinical success rates and increasing GBM patient survival.